Polymers that adhere well to biological surfaces (“bioadhesives”) under a variety of conditions are useful in several branches of medicine. One important use of bioadhesive polymers is in drug delivery systems, particularly oral drug delivery. Such bioadhesive polymers, for example, certain polyanhydrides, are useful for slowing the passage of drug-containing materials through the gastrointestinal tract. U.S. Pat. No. 6,197,346 to Mathiowitz et al. describes using bioadhesive polymers that have high concentrations of carboxylic acid groups, such as polyanhydrides, to form microcapsules or as a coating on microcapsules that contain therapeutic or diagnostic agents.
Polyanhydrides are bioadhesive in vivo, for example in the gastrointestinal (GI) tract, and can significantly delay the passage of drug-containing particles through the GI tract, thus allowing more time for absorption of drug by the intestine. The mechanism causing the anhydride polymers or oligomers to be bioadhesive is believed to be a combination of the polymer's hydrophobic backbone coupled with the presence of carboxyl groups at the polymer ends. Interaction of charged carboxylate groups with tissue has been demonstrated with other bioadhesives. In particular, pharmaceutical industry materials considered to be bioadhesive typically are hydrophilic polymers containing carboxylic acid groups, and often containing hydroxyl groups as well. CARBOPOL™, a high molecular weight poly(acrylic acid) available from B.F. Goodrich, Co., is an example of a hydrophilic bioadhesive material. Other classes of bioadhesive polymers are characterized by having moderate to high densities of carboxyl substitution. The relatively hydrophobic anhydride polymers frequently demonstrate superior bioadhesive properties when compared with the hydrophilic carboxylate polymers. For example, hydrophilic bioadhesive polymers tend to lose their effectiveness when wet, and especially when wetting is prolonged. Their reduced adhesion to surfaces in vivo and in vitro tends to diminish their effectiveness in enhancing drug delivery.
Natural adhesives for underwater attachment of mussels, other bivalves and algae to rocks and other substrates are known (see U.S. Pat. No. 5,574,134 to Waite, U.S. Pat. No. 5,015,677 to Benedict et al., and U.S. Pat. No. 5,520,727 to Vreeland et al.). These adhesives are polymers containing poly(hydroxy-substituted) aromatic groups. In mussels and other bivalves, such polymers include dihydroxy-substituted aromatic groups, such as proteins containing 3,4-dihydroxyphenylalanine (DOPA). In algae, diverse polyhydroxy aromatics such as phloroglucinol and tannins are used. In adhering to an underwater surface, the bivalves secrete a preformed protein that adheres to the substrate thereby linking the bivalve to the substrate. After an initial adherence step, the natural polymers are typically permanently crosslinked by oxidation of adjacent hydroxyl groups.
Extraction of these materials from organisms is not practical for commercial scale production. Attempts to reproduce the adherence have been made, typically using synthetic or genetically engineered polypeptides containing amino acid motifs derived from mussel adhesives, or natural marine materials. The synthetic protein materials have proved to be too expensive, or otherwise inadequate, to sustain commercial applications. For example, U.S. Pat. No. 4,908,404 to Benedict et al., describes grafting 3,4-dihydroxyphenylalanine (DOPA) to polyamines. However, the adhesiveness of these cationic water-soluble compounds is not much better than that of the parent polyamines, such as poly-L-lysine.
Relatively hydrophobic polymers frequently demonstrate superior bioadhesive properties when compared with the hydrophilic polymers. Nevertheless, there is a continued need for polymers with improved bioadhesive properties, particularly when the polymers and/or the surfaces are wet. In addition, there is a continued need for drug delivery systems that increase residence time in the GI tract, nasal mucosa, pulmonary mucosa, vaginal mucosa and other mucosa in a cost-effective manner.